The FDA’s recent approval of the Alzheimer’s drug aducanumab is a crucial crossroads in the continuing search for a cure for this devastating disease.
Federal regulators approved Biogen’s drug, through an accelerated process, earlier this month. The FDA’s approval came over the objections of its own scientific advisers, who had cited a lack of evidence for the drug’s effectiveness. (Several of those advisers have since resigned.) Patient advocates, on the other hand, welcomed the decision because, to date, there is no treatment that clearly slows down the progression of this disease afflicting 6 million Americans. Health policy experts worried, almost immediately, whether an expensive drug of unproven efficacy would send costs for Medicare and private insurance soaring.
But beyond the immediate effects of aducanumab alone, there is another question lurking after the FDA’s decision: Will this ultimately lead to more drug development for Alzheimer’s disease — or less?
“There could be big-picture harms for incentivizing drug development for truly innovative treatments,” Stacie Dusetzina, who studies drug pricing at Vanderbilt University, says. “It isn’t a very good signal for investors and innovators. ... Why should they push for something more complicated?”
Because one thing is clear: The evidence on aducanumab is mixed at best. It may, for some patients, slow the disease down. Experts are urging Biogen or Medicare itself to run more clinical trials to be sure. Either way, this should not be the end of the road in searching for a cure for Alzheimer’s disease.
Alzheimer’s patient advocates are optimistic that it won’t be. They believe one treatment finally getting FDA approval will encourage drug companies to keep investing in this space.
A representative for the Alzheimer’s Association offered the example of statins as a promising precedent. Since the first drug in that class was approved, six more statins have been introduced, each one more effective than the first. Likewise, the first HIV drug faced serious doubts about its efficacy, but its FDA approval ended up spurring more investment in that research area — and, with time, better treatment.
“When people are concerned about risk and whether things can get approved, this says, ‘No, pursue this. There is a major market here, and you need to enter that market as well,’” Robert Egge, chief public policy officer of the Alzheimer’s Association, told me. “To stand out, to win market share, you have got to make a business case that your treatment is more effective than the incumbent.”
He is not alone in that view. Three FDA officials, in a Washington Post op-ed explaining their decision to approve aducanumab, cited the approval of cancer drugs through the same accelerated approval pathway and the effect on subsequent research and development: “Even though not every drug worked as expected, these approvals have propelled progress forward.”
But there is an opposing view, shared by several experts I spoke to, that aducanumab could lead to less drug development. For one, drug makers may not think it’s worthwhile to invest the time and money to find more effective treatments. Biogen cleared a low bar to get the FDA to sign off on its drug, and now it’s setting the list price at nearly $60,000 a year.
“Maybe now some companies will see that they can get Alzheimer’s drugs approved, so they will start (or keep) investing in that space,” Holly Fernandez Lynch, who studies drug development at the University of Pennsylvania, told me over email. “Maybe some of their drugs will work. But they will have little incentive to prove that definitively if FDA doesn’t make them.”
On top of that, a lot of Alzheimer’s patients — millions, maybe — could now be prescribed aducanumab. Patients understandably take FDA approval to be a sign that a drug works and so, believing now that Biogen’s drug does, they could be reluctant to participate in future trials, whether confirmatory trials for this drug (in which case they risk being randomized to a placebo) or for different, unproven treatments.
“If you want to do a trial of different drugs, all your patients are still going to want aducanumab. So you have to start testing different drugs against it or in addition to it,” Lynch Fernandez says. “That’s going to make it a hell of a lot harder to tell if the new drugs work. There is a lot of negative potential when FDA lowers its standards.”
This is not a new concern. Three Penn researchers wrote about the same problem in 2019, warning that the FDA’s use of the accelerated approval pathway (the same process used to okay aducanumab) for cancer drugs could dampen future innovation.
They cited data showing that the FDA often does not force companies to complete the additional trials meant to confirm a drug’s efficacy. And even for those trials that are completed, they frequently find the approved drugs do not have a clinical benefit. On the issue of future innovation, the authors wrote:
Approval of ineffective drugs also crowds out innovation that might produce effective treatment. Once a drug has been approved for a certain indication, other companies and researchers might not invest resources in treatments related to the condition, believing that there is no market.
This is partly a result of how US insurers cover prescription drugs, which is generally not based on the value that the medication actually provides. Medicare generally covers any FDA-approved drug (though some experts are urging it to restrict or deny access for the Biogen drug, given the clinical record) and has few tools to limit the price it pays. Private insurers, on the other hand, will sometimes enter into arrangements with drug makers that give the insurer a financial incentive not to cover or to limit coverage for future drugs from the same class.
“The risk ... is that the first drug to market can block downstream innovation,” Robin Feldman, who studies innovation law at the University of California Hastings, told me. “This can be particularly problematic if the first-to-market drug is sub-optimal.”
There is one final complicating factor: The science upon which Biogen’s drug is based, known as the amyloid hypothesis, is still very much in dispute. It holds that plaque in the brain found in Alzheimer’s patients is in part responsible for the disease and that therefore removing plaque could help relieve the symptoms.
As recently as two years ago, when Biogen had halted its clinical trials for aducanumab because of poor evidence, scientists were questioning whether the amyloid hypothesis had been wrong, given how much time had passed without an effective treatment being found.
The question now following aducanumab’s approval, as Rachel Sachs at Washington University in St. Louis told me, is “whether the amyloid hypothesis is now being revived and more companies will be investing there, rather than in other hypotheses.”
It is possible to imagine a future in which companies do invest more in Alzheimer’s research after the FDA’s decision — but end up going all-in on a hypothesis that turns out to be wrong. Or the aducanumab approval could be the first step through a door that leads to a very effective treatment.
For now, no one can be sure which path we’re on.